Ester condensations



Patented May 16, 1939 UNITED STATES nsran CQNDENSA'IIONS Virgil 1.. Hensley, Niagara Falls, N. Y.,

assignor 'to E. I. du Pont de Nemours & Company, Wilmington, DeL, a corporation of Delaware No Drawing.S

Application June 25, 1936, erlal No. 87,257

Claims. (01. 260-593) i'his invention relates to the preparation of condensation products of organic compounds and more particularly to condensations of esters, or of esters with ketones or aromatic aldehydes.

Condensations of the above type, generally referred to as Claisen condensations, have long been known. Various condensing agents have been used in eflecting such condensations. Among the more common of these are metallic sodium and sodium alcoholate although sodamide, alkali metals other than sodium and their alcoholates, as well as alkali earth metals and alcoholates of alkali earth metals likewise have been used in certain instances.

Condensation reactions of the above type in general, have been unimportant except from a laboratory standpoint since the yields obtainable are relatively low when condensations are carried out by means of the usual condensing agents. 20 This is generally due to the occurrence of side reactions when an alkali metal or alkali earth metal is the condensing agent, orto the formation of byproduct alcohol when an alcoholate is employed.

An objectlof the present invention is to provide an improved condensing agent for use in condensation reactions involving esters, esters and ketones, and esters and aromatic aldehydes. Another object is to provide a condensing agent- 30 that does not efiect reduction of the reactants or reaction products during such condensation reactions. A further object is a method for carrying out condensations of esters, esters and ketones, and esters and aromatic aldehydes 35 whereby good yields of condensation products are obtainable. Other objects will be hereinafter apparent.

These objects are accomplished in accordance with the present invention by employing a metal 40 hydride of an alkali or alkali earth metal as the active condensing agent. I have found that such hydrides are highly eflective condensing agents in the above type of reactions in that conden- 'sations may be. eilected with high yields of the desired condensation products, which yields are unobtainable when the previously known con-- densing agents are. employed.

The alkali metal hydrides are especially well suited for the present use although hydrides of 50 the alkali earth metalslikewise may be advantageously employed. However, for reasons which will be hereinafter apparent I prefer to practice my invention using sodium hydride, preferably in a finely divided state, as the active condens- 1 ing agent.

Sodium hydride of suitable form and purity may be conveniently prepared according to the method described in U. s. Patent 1.9581012. The hydride obtained by this method is finely divided and has a purity of 99- 100%. It is best handled 5 as a powder moistened with the inert hydro,- carbon in which it has been prepared. when finely divided sodium hydride is covered with an inert hydrocarbon such as kerosene, it is practically inert to the atmosphere and may be handled without danger of spontaneously ignit- Sodium hydride prepared by the method of the above patentv possesses several advantages over sodium for use in the condensation reactions ll under consideration. Since these condensations generally require temperatures below the melting point of sodium, the latter. is generally subdivided by heating in an inert solvent before it is used. Usually this requires a solvent dififerent from that in which the reaction is to take place. On the other hand sodium hydride is finely divided as prepared and can be preserved indefinitely when -wet with the inert organic medium in which it is prepared. In addition sodium hydride possesses to a large measure all of the condensing powers of sodium itself but retains little or none of the reducing power of sodium towards carbonyl compounds such as aldehydes, ketones, and esters. The use of sodium '30 hydride therefore gives higher yields of condensation products since by-products due to the reduction of the reactants or reaction products are eliminated. Furthermore, condensation reactions eiiected by the use of sodium hydride as appear to be more direct than those effected with sodium since during a condensation with sodium the reaction mixture is deeply colored whereas when sodium hydride is used the reaction mixture remains white or at most only faintly 001-. 40

ored throughout. Finely divided sodium hydride moistened with benzene or kerosene is less haz-- ardous to handle, less hydroscopic, and more inert toconstituents of the air than is metallic sodium in the same state of subdivision.

Sodium hydride is generally better adapted for carrying out these condensationsthan is sodium alcoholate. Sodium hydride is essentially an alcoholate' in its reactions except that no alcohol is formed -as a by-product from; the hydride.

Since many of these reactions are equilibrium reactions with alcoholbeing a reaction product, sodium hydride is particularly usefulsince by its use a minimum amount of by-product alcohol is formed in the mixture. Also, in syntheses of Iii whereas in preparing ethyl acetoacetate sodium ethylate is required. on the other hand, sodium hydride is an excellent condensing agent for either reaction. Another advantage of sodium hydride over sodium alcoholate is that in many cases the reaction mixtures are more fluid when 7 the hydride is'u'sed than when an alcoholate is used.

Alkali and alkali earth metal hydrides and especially sodium hydride may be used to carry out condensations of saturated estersin general. Condensations may be eilected with saturated aliphatic or aromatic esters of low or high molecular weight provided that one of the ester members has a carbon atom adjacent to the carbonyl radical, which carbon atom is essentially aliphatic in reaction and holds at least one hydrogen atom. Obviously, condensations may be effected between molecules of a single ester or between molecules of two or more esters, it being essential only that one of the condensing members be of the type described in the line above. Esters which may be used in accordance with the present invention include, among others, the saturated esters of low molecular weight acids, such as acetic, propionic and butyric acids, and the saturated esters of the higher molecular weight acids, such as capric, lauric, myristic, palmitic and stearic acids.

Condensations likewise may be carried out in accordance with the present invention involving any ester and any ketone as the c'ondensing members it being only necessary that the ketone employed have a carbon atom adjacent to the carbonyl group which carbon atom is essentially aliphatic in reaction and which'holds at least one hydrogen atom. Examples of such ketones are, among others, acetone, methyl ethyl ketone, acetophenon'e, cyclohexanone, and alpha tetralon, etc. Any ketone which is aliphatic or hydroaromatic in nature may be employed as one of the condensing members.

In practicing the present invention to eifect condensations between esters and aromatic aldehydes, any aromatic aldehyde may be employed. Likewise any saturated ester may be used as oneof the condensing members provided the ester contains a carbon atom attached to the carbonyl group which is essentially aliphatic in reaction and which has attached thereto at least one hydrogen atom. a

In practicing my invention. the amount of alkali or alkali earth metal hydride employed may vary. when, for example, sodium hydride is employed one molmay be conveniently and efiectively used for effecting a condensation to produce theoretically one mol of reaction product although in-some instances it is advantageous to employ twice the above amounts. when the reaction is an equilibrium reaction with a mol of alcohol as a reaction product the use of two mols of metal hydride removes completely the by-product alcohol and thus effects a more complete reaction in the desired direction. In any case, the

, amount of hydride employed has but a slight effect on the final cost of the reaction product,

- especially when sodium hydride is used, since the molecular weight of the latter is relatively small. The following examples illustrate a few of the invention CaHsCH:CH.COOCaHs+NaOH+ V211:

Example II Benzaldehyde, .106 grams (1 mol), was added slowly to a suspension of sodium hydride, 28.8 grams (1.2 mols), man-excess of dry and essentially alcohol-free methyl acetate, which served as a'reactant and solvent. The rate of reactionwas controlled by the temperature, 10 0., and by the rate of addition of the aldehyde so that a slow but steady rate of hydrogen evolution was maintained. As soon as the calculated amount of hydrogen had been evolved the reaction mixture was acidified with acetic'acid and methyl cinnamate isolated by distillation. 116 grams or a 72% yield of methyl cinnamate resulted. Along with this 46.5 grams of methyl acetoacetate was obtained (a yield based on the sodium hydride used) The reaction involved may berepresented as follows:

CsH5CHO+CHaCOOCHa+NaH- I CaHsCH CH.COOCI'11 +NaOH+ /zH:

Example III A slurryof sodium hydride in xylene containing 1 mol of sodium hydride was treated with an excess (2.59 mols) of ethyl acetate. The latter OHiOO.CHi.C0.0C|H|+sodium acetate Example IV Acetone, 58 grams, was added slowly to a suspension of sodium hydride, 48 grams (2 mols) in 500 cc. of ethyl acetate at 0 C. After the addition of the acetone andthe theoretical amount of hydrogen had been evolved the reaction mixture was acidified with acetic acid and the acetylacetone precipitated as the copper salt,

(CsHvOr) 2011 This salt w...- filtered, washed, and dried. Upon regeneration, 85.5 grams or an 85.5% yield of acetylacetone, B. P. 1337f C. was obtained. The

reactions involved may be lows:

represented as fol- CHsCO.OH .CO.OH|+sodium acetate Example V s Acetone, 58 grams, was slowly added to a suspension of two mols of sodium hydride in 400 cc.

(excess) of methyl caprate. The reaction was complete at 20 to 25 C. after'lO minutes of moderate agitation. The reaction mixture was neu- 113-114 C. It analyzed 13.5% Cuas against a calculated value of 13.2 The reactions involve may be represented as follows:

CHI (CH1) |.C0.CH1C0 .CHa+sodium aceiai 6 Example VI An excess of methyl laurate, 321 grams, was

Na The sodium derivative uporr neutralization yields the free ketone. Example v11 Methyl myristate, 242 grams, was added to a 56.2% slurry of sodium hydride in kerosene containing one mol of sodium hydride and 1 cc. of methanol as catalyst. 'One-half mol of acetone was then slowly added to the mixture. The theoretical amount of hydrogen was evolved during 3 hours stirring at 30-40 C. The resulting mixture, worked up as in-Example V, yielded 112 grams or an 83.7% yield] of. heptadecane-2,4- dione, B. P. 196-19'l C. at 15 mm. pressure, M. P. 50-51 C. Its copper salt, (C11H31O2hCll, M. P. 117-118 C., analyzed 10.65% Cu as compared with the calculated value of 10.55%. The reaction involved may be represented as follows:

By neutralization of the reaction mixture th ketone is set free.

I Example v.11! Alpha tetralon, 93.? grams or 0.642 mol, was

" reacted with ethyl acetate in an excess of the latter as solvent using 1.28 mols of sodium hydride as the condensing agent. After stirring the mixture for 1.5 hours at 4-5 C. and then increasing the temperature to 27 C. during the next 1.5

hours the reactionmixture was neutralized as in Example V and the reaction product, acetyl alpha tetralon, separated by crystallization. A yield of 101 grams, or 84%, of the compound, M. P. 56-57 0., was obtained. 'Its copper salt, (CnHuOzhCu,

M. P. 204-205 C., analyzed 13.5% Cu as compared with a calculated value of 13.2%. The reaction involved may be represented as follows rn+cmcoocmt+zmn Example IX Methyl laurate, 107 grams in cc. of refined kerosene containing 1 cc. of methanol as catalyst, was heated with 13 grams of'sodium hydride at C. for 2 hours. During this time the theoretical amount of hydrogen was evolved. The reaction mixtln'e was then acidified with glacial acetic acid and the beta-keto methyl ester separated by crystallization. The yield of methyl laurolaurate was practically quantitative. After recrystallization, this beta-keto ester melted at 38-40 C. By ketonic hydrolysis the known monoketone, lauron, (C10H21) 2C0,M. P. 69-70" C. was obtained in a 95.2% yield. The reaction involved may be represented as follows:

The addition of acid liberates the free beta-keto ester.

Example X Example XI Methyl palmitate, grams in 100 cc. of refined kerosene with 1 cc. of methanol as catalyst, was heated to 120-130" C. for 5 hours. By isolation as in Example IX, 124.4 grams or a yield of 97.6% of crude methyl palmitopalmitate was obtained. After recrystallization the pure beta-keto methyl ester melted at 54-55 C. By ketonic hydrolysis the already known ketone, palmiton, (C15Ha1) CO, M. P. 79-80" C., was obtained in a 95.1% yield. The reaction involved may be represented as follows:

- smm ze x11 Methyl stearate, 149 grams in 100 cc. of refined kerosene as solvent, was treated with 12 grains of sodium hydride at 130-140 C. using 1 cc. of

methanol as catalyst. After a. reaction period of 3.5 hours the product was isolated as in Example 11:. A 94.2% yield of crude methyl stearostearate was obtained which upon recrystallization melted at 60-62' C. By ketonic hydrolysis the known ketone, stearon, M. P. 88-89 C., was obtained in an 87.3% yield. The reaction involved may be represented as follows:

In practicing the present invention, the ester employed as one of the reaction constituents may be conveniently used as the solvent medium for the reaction. However, other solvents which do not-react with the reactants or reaction products or with the metal hydride condensing agent may be employed. For example, among others, xylene, kerosene, ethers and inert hydrocarbons in general may be advantageously used, especially when the ester reaction constituent is a solidand when the reaction temperature required is relatively high. When the ester reaction constituent has a high boiling point and is diflicult to distill, the use of an inert solvent in place of an excess of the ester to act as the reaction solvent obviates the necessity oi separating the excess ester by distillation irom the reaction mixture.

While I have illustrated in the above examples condensations of aldehydes or ketones with esters eiiected at temperatures ranging from '-10 to 40 C. and ester condensations effected at temperatures ranging from 20 to 140 C., it is to be understood that the above temperature ranges are at a temperature of C. or lower, whereas similar condensations involving esters of higher molecular weight acids may be carried out in accordance with the present invention by using higher reaction temperatures.

I prefer to use sodium hydride as condensing agent in practicing my invention because it is relatively cheap and more conveniently prepared in a suitable state than are other alkali or alkali,

earth metal hydrides. Furthermore, I prefer to employ an alkali metal hydride rather than an alkali earth metal hydride because the alkali metal hydrides may be prepared conveniently at relatively low temperatures in a finely divided state. However, alkaliearth hydrides, such as calcium hydride, may be used effectively as the condensing agent in my process.

Many of the compounds which may be prepared in accordance with the presentinvention have long been important in laboratory syntheses but because of their relatively high cost have found little, it any, use in commercial chemical These compounds may be prepared elatively cheaply and in good yields by use ofdehydes.

the present condensing agents which makes pos- It is understood that the present invention is not limited by the modifications and examples herein disclosed and that any'adaptation or modiflcation apparent to a skilled chemist is intended to come within the scope and spirit of the invention.

I claim:

1. A process for preparing ester condensation products comprising reacting a saturated ester with a ketone in the presence of a metal hydride of a metal of the group consisting oi alkali metals and alkali earth metals, said ketone having a carbon atom adjacent to the carbonyl group which carbon atom is essentially aliphatic in reaction'and has attached thereto at least one hydrogen atom.

2. A process for preparing ester condensation products comprising reacting a saturated ester with a ketone in the presence of sodium hydride. said ketone having a carbon atom adjacent to the carbonyl group, which carbon atom is essentially aliphatic in reaction and has attached thereto at least one hydrogen atom.

3. A process for preparing ester condensation products comprising suspending finely divided sodium hydride in a saturated ester, adding to said suspension a ketone having a carbon atom adjacent to the carbonyl group which is essentially aliphatic in reaction and which has attached thereto at least one hydrogen atom, acidifying the resulting mixture and isolating the resulting condensation product.

4. A process for preparing ester condensation products comprising reacting in the presence of an alkalimetal hydride a saturated ester with an organic carbonyl compound having attached to the carbonyl group a hydrogen atom or a. carbon atom to which is attached at least one hydrogen atom, said compound being selected from the group consisting of ketones and aromatic a1 5. A process for preparing ester condensation products comprising reacting in the presence oi sodium hydride a saturated ester with an organic carbonyl compound having attached'to the carbonyl group a hydrogen atom or a carbon atom comprising methyl caprate and sodium hydride at a temperature of about 20-25 C., maintaining the resulting mixture at said temperature untilthe reaction is complete, acidifying the reaction mixture and isolating tridecane-2,4-dione.

8. A process for the preparation of heptadecane-2,4-dione comprising adding acetone to a mixture comprising methyl myristate and sodium hydride at a temperature of about 30-40" C., maintaining the resulting mixture at said temperature until the reaction is complete, acidifying the reaction mixture and isolating heptadecane-2,4-dione.

YIRGIL L. HANSLEY. 

